Sleep is an evolutionarily conserved behavior that is important for neural performance and function, yet the genes and neurons that regulate sleep are poorly understood. The best-characterized sleep regulators are the hypocretin neuropeptides, which promote wakefulness and inhibit sleep. Loss of hypocretin neurons causes narcolepsy, an incurable neurological disorder characterized by excessive daytime sleepiness and fragmented sleep/wake states. Hypocretin neurons thus play a critical role in regulating sleep, but virtually nothing is known about factors that regulate their specification. Preliminary studies in the zebrafish, Danio rerio, have identified 19 genes with enriched expression in hypocretin neurons. I will test the hypothesis that some of these genes are necessary and/or sufficient to specify the hypocretin neuronal fate. Identifying such factors will greatly expand our understanding of hypocretin neuronal development, and may elucidate how these neurons are assembled into a functional sleep circuit. Ultimately, these experiments could lead to novel therapies that prevent or reverse the loss of hypocretin neurons in patients with narcolepsy. PUBLIC HEALTH RELEVANCE: Hypocretin neuropeptides play an evolutionarily conserved role in promoting wakefulness and inhibiting sleep. The loss of hypocretin neurons causes the sleep disorder narcolepsy, which has no known cure and is treated symptomatically. Using zebrafish as a simple vertebrate model, I will investigate the genetic basis of hypocretin neuronal development, which will improve our understanding of how sleep regulatory circuits are established and may lead to long-term, cellular therapies for narcolepsy.